Reduction of steroid epoxides



Patentecl June 3, 1952 REDUCTION OF STEROID EPOXIDES Placidus Plattner, Zurich, Switzerland, assignor to Ciba Pharmaceutical Products Inc., Summit, N. J.

No Drawing. Application September 22, 1949, Serial No. 117,275. In Switzerland September 9 Claims. (01. 260-397.1)

This invention relates to the manufacture of hydroxy compounds by the hydrogenative splitting of vicinal epoxides, i. e. epoxides containing the grouping It is known that in the reduction of vicinal epoxides dimculties are often encountered which in most cases consist in that non-uniform reaction products are formed. Moreover, in the case of diflicultly hydrogenatable vicinal oxido-bridges, the expectation is that under the energetic reaction conditions employed the oxido-oxygen may be completely eliminated.

Synthetic processes for the manufacture of hydroxy compounds, in particular for the introduction of single hydroxy groups into the struc-- ture of steroids, are already known and among these processes splitting by reduction of oxidocompounds is occasionally encountered. In the case of the steroids, there are primarily involved those of the sexual andsuprarenal hormone series and also numerous representatives of the strophanthus, digitalis, scilla toad venom and cardiac poisons which contain hydroxyl groups at certain positions of the cyclopentanopolyhydrophenanthrene structure, which hydroxyl groups are of importance for the .physiological properties of the mentioned compounds. The hitherto known methods of reductive splitting of oxides lead, however, to the desired result, only in quite a limited number of cases.

Thus, for example, it has not been possible by reduction of 4,8,5-oxido- 5,6}9-oxido-steroids to arrive at 5-hydroxy-coprostane derivatives which correspond in configuration, for example, to strophanthidin and until now no synthesis has become known which leads in this manner to derivatives of 5-hydroxy-coprostane. The fi-oxides of allocholesterol and of epi-allo-cholesterol, for example, yield 3,4-dihydroxy-cholestanes on catalytic reduction.

It has also hitherto notbeen possible, by reduction of 16,17a-oxido-steroids, the configuration of which at the C-atoms l6 and I1 has moreover not yet been established, to produce 17ahydroxy compounds which correspond to the natural 17-hydroxy-steroids of the suprarenal hormone series. In other cases it is true that it has been possible to realize the reductive splitting of the oxides in the desired direction, but the yields produced were often low and mixtures of isomers were produced which were dlflicult to separate. Whereas 11,9,12p-oxido compounds of the cholanic acid series likewise yielded mixtures on reduction, the 3a-acetoxy-9,1l-oxido-cholanic acid methyl ester was hardly affected at all by catalytically activated hydrogen.

A primary object of the present invention is the realization of the reductive splitting of those steroid epoxides which have hitherto withstood other reduction methods, such as for example catalytic hydrogenation or reduction with sodium and alcohol.

This object, and others which will become evident asthe disclosure of the invention is hereinafter developed, is realized according to the present invention by the expedient of effecting the desired reductive. splitting with the aid of reactive metal hydrides as the reducing agents. More particularly, use is made in this regard 0f the bimetal hydrides such as alkali metal-aluminum hydrides, and primarily of lithium-aluminum hydride, further also of sodiumor lithium-boron hydride. In this manner, it has been found that the oxido bridges in vicinal epoxides can be split by hydrogenation by way of a mild reaction which can be easily carried out in a uniform manner.

By means of the present process success has 'been achieved, in particular, in the reductive splitting of certain steroid epoxides which have hitherto withstood other reduction methods, such as those aforementioned.

Thevicinal epoxides, serving as starting materials, belong to the steroid series, especially to the 10,13 dimethylcyclopentano polyhydrophenanthrenes which may be substituted in any desired manner. The present process will be employed primarily, i. e. with especial advantage, in the case of 45-, 11. 14,15-, 16,17-, and 20,21- steroid epoxides which could not hitherto be converted into the desired end products at all by customary methods or only in poor yield. Thus, the present process has made it possible to achieve for the first time the partial synthetic production of 3,9,5-dihydroxycoprostane, starting from 3 3- hydroxy-4,5-oxido-cholestane and also the reduction, in smooth manner, of 16,17a-oxido-steroids Y to l7a-hydroxy compounds and of 11,12-oxidosteroids to uniform hydroxy derivatives.

The reduction is advantageously carried out in the presence of a diluent which-may Vary according to the metal-hydride used. Thus-the reduction with an alkali metal-aluminum hydride, such as lithium-aluminum hydride, is efi'ected' in the presence of an indiiferent anhydrous organic solvent in which the metal hydride is soluble, in particular in the presence of ether-or also tetra-hydro- 3 furane, butyl ether and the like. When working, for example, with sodium-boron hydride, the reduction is advantageously carried out in the presence of water.

The following examples illustrate the invention, the parts being by weight unless otherwise stated and the relationship of parts by weight to parts by volume being the same as that the kilogram to the liter:

EXANLPLE 1 3/3,17a,20p-trihydroxy 5 allo-pregnane (Reich:

steins Substance J) ,3fi,20p-diacet0a:y-17a-hydroxy-5-aZl0-pregnane (Reichsteins, Substance J-diacetate) and 3,3,20a-diacet0my-1h-hy droxy-5-aZlo-pregnane (Reichsteins' Substance O-dz'acetate) of the formulae Substance O-diacetate 7 parts of 3fi,-acetoxy-16,17a-oxido-20-keto-5- al orpregnane. of melting point 181 C. (produced, for example;. by reaction of A 3;3-acetoXy-20- keto-5 -allo-pregnane with perbenzoic acid or hydrogen peroxide in glacial acetic acid) are dissolved in, 300; parts by volume of absolute ether and added drop by drop with good stirring-to a solution of 4 parts of lithium-aluminum hydride in 600 parts by volume of dry ether. When the fairly vigorous reaction has subsided, the solution is heated, to. boiling for another hour, and then water and finally dilute sulfuric acid are carefully added thereto. The ethereal layer is washedineutral with water. dried and evaporated; The crystallized residue can be purified by recrystallization from methanol-water and then meltsat 223-224? C, It consists of. 3/3,17a,20fitrihydroxy- 5-a1lQ-pregnane (Substance J of Reichstein, 1938),.

From the mixture of the mother liquors, b acetylation and; chromatographic purification, the following 17a,- hydroxy-steroids can be isolated: 3,3,205-diacetoxy 17a-hydroxy-5-allopregnane of melting point 161 C. (Substance J -diacetate of Reichstein), and 3p,20a-diacetoxy- 1'7a-hydroxy-fi-allo-pregnane of melting point,

243 0; (Substance O-diacetate of Reichstein,

In the same manner, 3,3-hydroxy-16,17a-oxido- 20-keto-5-allo-pregnane of melting point, 181- 1 4' tion products are again Reichstein's Substances J and 0.

EXAMPLE 2 35,17a,20,21-tetrahydro.ry 5 allo pregnane (Reichsteins Substance K). of the formula CHzOH In the same manner as that set forth in Example 1, 3,3,21-diaoetoxy-16,17a-oxido-20-keto-5- allo-pr'egnane of melting point 153-154 C. can be reacted with lithium-aluminum hydride. The product oithis reaction is 3p,17a20,21,-tetrahydroxy-B-allo-pregnane (Reichsteins Substance K); of melting point 198-200 C.

Other pregnanes which contain other acyloxy groups or which are substituted by free hydroxyl groups instead of the esterified hydroxyl groups may also be subjected to a similar reduction.

EXAMPLE 3 35,5-dz'hydrorcy-coprostaneof the formula 7 parts of 3fl-,-acetoxy-4fl,5-oxido-coprostane of melting point 89?, C. (produced by catalytichydrogenation of 3 ketoriafi oxido-coprostane, and, subsequent acetylation, or, preferably, by. oxida: tion, of A -3Bracetoxy-cholestene with mat-acids),

are'dissolved in 200 parts'by, volume, of absolute ether and added. dropby drop withfgood stirring to a solution of 5 parser lithium-aluminum hy-l dride'in 500 parts byjvolume of dry ether -The reaction mixture is thoroughly stirred for. 15,

minutes. and then. 200. partsby volume of, water and finally 400 parts by volume, of 10 percent.

sulfuric acid are added drop by drop. After the,

addition of more ether, the ethereal. layer is separated, washed neutral with water, dried. and.

evaporated. The crystallized residue, after being twice recrystallized from ,,ethanol, is obtained,

3a,5-dihydromy-coprostaneofthe formula parts of 3a-acetoxy-4fl,5-oxido-coprostane' of melting point. 68-70 0. (produced by hydrogenation of 3 keto-4fl,5-oxido-coprostane and subsequent acetylation or, preferably, by oxidation of A -3a-acetoxy-cholestene with per-acids) are dissolved in 200 parts by volume of absolute ether and added drop by drop with good stirring to a solution of-5 parts of lithium-aluminum hydride in 500 parts by volume of dry ether. The reaction mixture is worked up as described in the preceding examples. The crystallized crude product is. after being twice recrystallized from methanol, obtained in the pure condition and melts at 192-193 C. ;It constitutes 3a,5-dihydroxy-coprostane. The 3-mono-acetyl derivative of this substance melts at 147-148" C.

EXAMPLE 5 3a,5-dihfUdTO.I!Z/- and 35,5-dihydromy-ooprostane 5 parts of 3-keto-4p,5-oxido-coprostane of melting point 116-117 C. (produced by oxidation of cholestenone with alkaline hydrogen peroxide) are dissolved in 200 parts by volume of absolute ether and added drop by drop with good stirring to a solution of 5 parts of lithium-aluminum hydride in 500 parts 'by volume of dry ether. The working up of the reaction mixture takes place as in the preceding examples. For purification the crude pro duct is subjected to chromatographic procedures. In this manner the isolation is achieved of 3.5 parts of '3fi,5-dihydroxy-coprostane of melting point 192-193 C. (see Example 4) and 1.3 parts of 3,3,5-dihydroxy-coprostane of melting point 148-149" C. (see Example 3).

EXAMPLE 6 35,5-dihydroxu-ch0lestane of the formula OreHzo I HO on 1 part of a-OhOlBStBI'Ol oxide acetate of melting point 92-95 C. is dissolved in 500 parts by volume of absolute ether and added drop by drop with good stirring to a solution of 1 part of lithiumaluminum hydride in 150 parts by volume of dry ether. The reaction solution is heated for minutes to boiling, then drop by drop 100 parts by volume of water and finally 100 parts by volume of 10 per cent. sulfuric acid are added. The ethereal solution is washed neutral with'water, dried and evaporated. The crystalline residue can be purified by recrystallization from ethyl acetate and then melts at 216-217 C. It constitutes 33,5-dihydroxyecholestane.

EXAIVIPLE '2 31?,(So-diacetowu-cholestane of the formula OMEN alum'inum hydride'in 6 00 parts by volume of dry ether. The working up of the reaction solution takes place as in Example 6. For further purification the 35,6,9-dihydroxy-cholestane is converted in known manner into the diacetate and this separated from Joy-products by adsorption on aluminum oxide. In this manner is achieved the isolation of 2.5 parts of pure 35,6,9-diacetoxycholestane of melting point -131 C.

EXAMPLE8 Ba-hydroxy-choZestane and 2, -dihzldroawh estane of the formulae and 10 parts of 2,3a-oxido-cholestane of melting point 105 C. are dissolved in 100 parts by volume of absolute ether, and to the resultant solution is added with stirring a solution of 2 parts of lithium-aluminum hydride in 300 parts of absolute ether. After the addition, the whole is further stirred for 40'minutes longer and heated for a further 10 minutes. The reaction mixture is treated with water, then with dilute sulfuric acid and extracted with ether. By chromatographic purification, 8 parts of Ba-hydroxy-cholestane and 1.5 parts of 2,3-dihydroxy-eholestane are isolated.

EXAMPLE- 9 zp-hydroxyechole stane of the formula EXAMPLE .10

3a,5-dihydro:cy-cholestane of the formula CiaHzo HO- 0H 10 parts of 3 -hy Xy-5fi -oxid0-ch0lestane of melting point 122 C. are dissolved in 250 parts by volume of absolute ether, and 5.5 parts of lithiumaluminum hydride in 300 parts by volume of dry ether are added drop by drop with stirring. Working up as in Example 6 yields 8 parts of 311,5edihydroxy-cholestane of melting point 3 11,5 '-dihg' droa:y-copro'stdue and. r J 3a.,6-dih'g/dromychoZestitne. -oj. the formulae.

and

To 9 parts of 3a-hydroxy-5,6p-oxldo-coprostane of melting point 160 16-3 C. in 150 parts of absolute ether is added a solution'of 4.5 parts of lithium-aluminum hydride. Afteranhour the reaction mixture is worked up as described in Example 6. By chromatographic purification, 1 part of 3a-hydroxy-cholestane, 2 parts of 3a,5-dihydroxycoprostane and 5 partstofb3a,6/idihydroxy-cholestaneare isolated;

3 parts of 3a-acetoxy-11,12/3-oxido-cholanicacid-methyl ester or melting point. 150-154 Chara dissolved in 1000- parts by volume of anhydrous ether. and the resultant. solution added dropwise and with thoroughsti-rring to a solution of- 8 partsof. lithium-aluminum hydride in 1000-parts byvolume otabsolute-ethen: The reaction mixture is. worked-upas in-Example 6; The obtained product, after recrystallization from ethyl acetate, melts at 186-188 C; and is identical with the reduction product of 3a-acetoxy-11fl-hydroxy-cholanic-acid-methyl"ester (melting point 146 C.) with lithium-aluminum hydride. The substance constitutes a triol and yields a crystallized diacetate and dibenzoate. The reduction is advantageously carried out in tetrahydrofurane or dioxane at a raised temperature in lieu of ether.

EXAMPLE. 13

2 parts by weight:of:3a-acetoxy 11,12aFoxido;- cholanic-acid-methyt ester'of melting point 141".

C. are dissolved in. 1'80"parts by volume of dry ether, the solution addeddropwiseand'with thorough stirring to a solution of 2.2'parts'of lithium aluminum. hydridein. 120 parts. by volume. of

may be used 11,1 2-oxido-cholanic acid esters con...

taming a free hydroxy. group-instead ofan-ace-- toxy group inB-position; I

EXAMPLEM" 1 [part of; A -3-p-acetoxy-14,15p-oxido 20 keto-5-allo-pregnene is dissolved in a mixture of" 10 parts by volume of ether and 10 parts by volume'of benzene, and the solution added dropwise andwith thorough"stirring to'a solution 011 part of-lithium-aluminum hydride in parts by volume-ofabsolute ether. Thereaction mixture is worked up-as described in Example 6, and. the crude product'is adsorbed on 40'parts o1 aluminum" oxide in order to purify the product. The benzene-ether eluates yield a compound which, after recrystallization from ether, melts at 174 C. and corresponds tothe empirical formula CziHizOs. Asecond substance or the formula 02111340: is elutedwith ether. It melts at'223- 224 C., after recrystallization from ethyl acetate.

EXAMPLE 15 3a,5-dihydroxy-cholestane of the formula I 1 ltHzO HO-' on 0.54 part of crude 3a-acetoxy-4u,5-oxido-cholestane of the melting point 88-9I C. is dissolved in parts by volume of dry ether, and the resultant solution then added dropwise and with thoroughstirring to a solution of 0.54 part of lithium-aluminum hydride in 20 parts by volume of anhydrous ether. The reaction mixture is stirred for another 20'minutes, and then 10 parts by volume of water, followed by-10' parts by volume of 10% sulfuric acid, are carefully added Y thereto. After dilution with ether, the ethereal layer is washed with water and sodium bicarbonate solution, dried andevaporated. The residue, after recrystallization from alcohol, yields 312,5- dihydroxy-cholestane of melting point 193-195 C.

EXAMPLE 16 35,5-dihydroxy-cholestane of the formula l on 0.13 part. of -acetoxy=-4a,5-oxido-cholestane of melting point 117 C. is reduced, in the same way as: the 311-acetoxy-4a,5-oxido'-cholestaneof Example 15,. with 0.13 part of lithium aluminum hydride in absolute ether. Working up, as in the same. example, yields a crystallized residue which melts at223'-225 C. and is 3,8,5-dihydroxy-cholestane.

EXAMPLE-1'7 '7 parts of A -3fl-acetoxy=14,15p-oxid0-20- keto-5-allo-pregnene are dissolved in 100 parts by volume of methanol'and 50 parts by volume of chloroform, and the resultant solution is then added while stirring vigorously to a solution of 4 parts of sodium-boron hydride in 50 parts by volume of water and 100 parts by volume of dioxane. The reaction is carried out at 40 C. and the reaction mixture is then heated for 30 minutes to C. Working up of the solid product is carried out after the manner of Example 6. The crude product is dissolved in 200 parts by volume of glacial acetic acid, and then oxidized in conventionalmanner in thecold with 3 parts of chromium trioxide. Theresultant reaction product,af-ter recrystallization from methanol, melts 9 at 149-150 C. and corresponds to the empirical formula C2aH34O'4.

EXAMPLE 18 2 parts of crude A -17,20-oxido-pregnene-on- (3) (isomeric mixture) of the melting point 177- 188 C. are dissolved in 180 parts by volume of ether, and the resultant solution is then added dropwise and with thorough stirring to a solution of 2.2 parts of lithium-aluminum hydride in 120 parts by volume of absolute ether. After heating it for a short time, the reaction mixture is worked up in the manner described in Example 6. The resultant product, after recrystallization from methanol-water, melts at 150 C. It contains a double bond and two hydroxyl groups and yields a crystallized monoacetate.

In an analogous manner, there may also be reduced other 17,20-hydroxy-pregnanes, containing substituted or unsubstituted hydroxy groups, for example, in the 3- or in the 3- and 11- or 12- position.

Having thus disclosed the invention, what is claimed is:

1. A process for the preparation of a hydroxy steroid compound, which comprises subjecting the corresponding steroidal vicinal epoxide to the reductive action of a member selected from the group consisting of alkali metal-aluminum hydride and alkali metal-boron hydride, as reducing agent, whereby reductive splitting of the epoxide group takes place.

2. A process according to claim 1, wherein the reducing agent is lithium-aluminum hydride.

3. A process according to claim 1, wherein the reducing agent is sodium-boron hydride.

4. A process according to claim 1, wherein the reducing agent is lithium-aluminum hydride, and the reduction is effected in an anhydrous, inert organic solvent.

5. A process for the preparation of a hydroxy steroid compound, which comprises subjecting the corresponding steroidal vicinal 16,17-epoxide to the reductive action of a member selected from the group consisting of alkali metal-aluminum hydride and alkali metal-boron hydride, as re- 10 ducing agent, whereby reductive splitting of the epoxide group takes place.

6. A process for the preparation of a hydroxy steroid compound, which comprises subjecting the corresponding steroidal vicinal 11,12-epoxide to the reductive action of a member selected from the group consisting of alkali metal-aluminum hydride and alkali metal-boron hydride, as reducing agent, whereby reductive splitting of the epoxide group takes place.

7. A process for the preparation of a hydroxy steroid compound, which comprises subjecting the corresponding steroidal vicinal 14,15-ep0xide to the reductive action of a member selected from the group consisting of alkali metal-aluminum hydride and alkali metal-boron hydride, as reducing agent, whereby reductive splitting of the epoxide group takes place.

8. A process for the preparation of a hydroxy steroid compound, which comprises subjecting the corresponding steroidal vicinal 5,6-epoxide to the reductive action of a member selected from the group consisting of alkali metal-aluminum hydride and alkali metal-boron hydride, as reducing agent, whereby reductive splitting of the epoxide group takes place.

9. A process for the preparation of a hydroxy steroid compound, which comprises subjecting the corresponding steroidal vicinal 17,20-epoxide to the reductive action of a member selected from the group consisting of alkali metal-aluminum hydride and alkali metal-boron hydride, as reducing agent, whereby reductive splitting of the epoxide group takes place.

PLACIDUS PLATTNER.

REFERENCES CITED UNITED STATES PATENTS Name Date Logemann Mar. 27, 1945 OTHER REFERENCES Nystrom et al., Jour. Am. Chem. Soc, 69, 1197- 1199 (1947) e Number 

